It is well known that many drugs, if taken orally, are destroyed on the first pass through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the system is not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems has met with increasing interest by researchers in the pharmaceutical drug-delivery field.
In attempting to produce the invention described in detail infra, the inventors incorporated a pharmaceutically active drug (nitroglycerin) into an acrylic adhesive in order to form a transdermal drug delivery system. After incorporating the drug into the adhesive polymer, the inventors found that the adhesive dissolved. Accordingly, the structural integrity of the dosage unit formed was lost and the rate of release of the nitroglycerin therefrom could not be controlled. Since the dissolution of the adhesive appeared to be caused by the incorporation of the nitroglycerin, the inventors decreased the amount of nitroglycerin in order to maintain the structural integrity of the adhesive and prevent it from dissolving. The inventors found that, by decreasing the amount of nitroglycerin in the adhesive, dissolution could be prevented and a transdermal delivery system could be prepared. However, such a system contained a relatively small amount of nitroglycerin. Accordingly, when the system was applied to human skin, although the adhesive properties of the system were maintained, the release of nitroglycerin was so slight as to not have the desired effect on the patient to which the system was applied. The inventors have since found that others apparently attempted the same procedure and also found that the amount of nitroglycerin released was not sufficient or not controllable due to dissolution (see Ito, et al. in U.S. Pat. No. 4,421,737, column 7, line 68--column 8, line 2; Canadian Patent 1,144,070, page 14, lines 3-5, and U.S. Pat. No. 4,420,470 at column 1, lines 23-34.)
In an attempt to solve the above-referred to problems, the inventors tried various types and combinations of adhesive polymers without success. The inventors found that with certain polymers and combinations thereof, the polymer composition formed was simply too hard and insoluble with respect to the solvent-acting drug such as nitroglycerin. Accordingly, the polymer composition did not have sufficient adhesive properties in order to adhere firmly to human skin and could not incorporate therein a sufficient amount of the solvent-acting drug such as nitroglycerin. Other polymer compositions that did have sufficient adhesive properties could not maintain their structural integrity when standing alone or when exposed to human skin and body heat over a substantial period of time and further became dissolved when sufficient amounts of nitroglycerin were incorporated therein. The present inventors found that these problems could be solved by including within the composition a cross-linking agent in a relatively small amount. The cross-linked adhesives disclosed in U.S. Pat. Nos. 4,374,164 and 3,475,363 are useful in connection with the present invention and these patents are incorporated herein by reference for purposes of disclosing such cross-linked adhesives.
The inventors noted that by including large amounts of cross-linking agents into polymer compositions that included solvent-acting drugs incorporated therein, the adhesive properties of the compositions were lost, i.e., the composition lost its tackiness. If insufficient amounts of cross-linking agent were included in the composition, the composition was dissolved.